Pulmonary arterial hypertension (PAH) is a serious cardiopulmonary disease characterized by progressive narrowing of the small pulmonary arteries and elevated pulmonary artery pressure, which can lead to right heart failure. Much has been learned about the rare familial form by the identification of predisposing genes, but the molecular basis of associated PAH (APAH) in the context of congenital heart defects or connective tissue disorder remains largely unknown. Even in familial PAH, the penetrance of these mutations is low and the additional genetic or environmental factors that contribute to the etiology of PAH are not well understood. Our approach focuses on understanding both the germline genetic variation that predisposes to PAH and also somatic changes arising within the lung that may contribute to the onset and/or progression of the disease. We have shown that in pulmonary artery endothelial cells (PAEC) isolated from explant lung tissue, one-third of PAH cases harbor large-scale chromosome abnormalities. This is a minimum estimate, since there are likely more subtle alterations that are below the resolution of the analyses we have performed thus far. Levels of DNA damage were markedly higher in PAH cells than controls, not only in PAEC but also in peripheral blood mononuclear cells (PBMC). The level of damage correlated strongly with the amount of reactive oxygen species (ROS). Patients' cells were also significantly more sensitive to DNA damaging chemotherapeutic agents than controls. Similar abnormalities were seen across heritable, idiopathic and associated PAH cases. Remarkably, we discovered that PBMC from relatives of patients show the same profile of increased ROS production, mutagen sensitivity and DNA damage, suggesting that it may be a genetically determined trait. Our central hypothesis is that PAH patients share an intrinsic susceptibility to DNA damage that pre-dates the onset of PAH, predisposing to genetic alterations that contribute to vascular remodeling following endothelial cell injury. The aims of this study are to (1) determine the profile of DNA damage and repair in PAH cells, (2) identify the molecular basis of increased ROS and DNA damage, and (3) identify the genetic factors underlying increased DNA damage in PAH.